Parathyroid hormone (xe2x80x9cPTHxe2x80x9d) is a polypeptide produced by the parathyroid glands. The mature circulating form of the hormone is comprised of 84 amino acid residues. The biological action of PTH can be reproduced by a peptide fragment of its N-terminus (e.g. amino acid residues 1 through 34). Parathyroid hormone-related protein (xe2x80x9cPTHrPxe2x80x9d) is a 139 to 173 amino acid-protein with N-terminal homology to PTH. PTHrP shares many of the biological effects of PTH including binding to a common PTH/PTHrP receptor. Tregear, et al., Endocrinol., 93:1349 (1983). PTH peptides from many different sources, e.g., human, bovine, rat, chicken, have been characterized. Nissenson, et al., Receptor, 3:193 (1993).
PTH has been shown to both improve bone mass and quality. Dempster, et al., Endocrine Rev., 14:690 (1993); and Riggs, Amer. J. Med., 91 (Suppl. 5B):37S (1991). The anabolic effect of intermittently administered PTH has been observed in osteoporotic men and women either with or without concurrent antiresorptive therapy. Slovik, et al., J. Bone Miner. Res., 1:377 (1986); Reeve, et al., Br. Med. J., 301:314 (1990); and Hesch, R-D., et al., Calcif. Tissue Int""l, 44:176 (1989).
In one aspect, the invention features a peptide of the formula (I), 
wherein
A1 is Ser, Ala, or Dap;
A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Acc, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, Acc, or Nle;
A11 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly, Acc, or Aib;
A15 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Acc, Cha, or Met;
A22 is Acc or Glu;
A23 is Trp, Acc, or Cha;
A24 is Leu, Acc, or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, Acc, or Cha;
A28 is Leu, Acc, or Cha;
A29 is Gln, Acc, or Aib;
A30 is Asp or Lys;
A31 is Val, Leu, Nle, Acc, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynaphthylalkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2; provided that at least one of A5, A7, A8, A11, A12, A15, A18, A21, A22, A23, A24, A27, A28, A29, and A31 is Acc; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the immediately foregoing peptide is where A3 is Ser; A5 is Ile or Acc; A7 is Leu, Acc, or Cha; A8 is Acc, Met, Nva, Leu, Val, Ile, or Nle; A11 is Leu, Acc, or Cha; A12 is Acc or Gly; A15 is Leu, Acc, or Cha; A16 is Asn or Aib; A17 is Ser or Aib; A18 is Acc, Met, or Nle; A21 is Val or Acc; A27 is Lys, hArg, Acc, or Cha; A31 is Val, Leu, Nle, Acc, or Cha; A32 is His; A33 is Asn; A34 is Phe, Tyr, Amp, or Aib; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the immediately foregoing peptide, designated Group B, is where A5 is Ile or Ahc; A7 is Leu, Ahc, or Cha; A8 is Ahc, Met, or Nle; A11 is Leu, Ahc, or Cha; A12 is Ahc or Gly; A15 is Leu, Ahc, or Cha; A18 is Met or Ahc; A21 is Val or Ahc; A22 is Glu or Ahc; A23 is Trp, Ahc, or Cha; A24 is Leu, Ahc, or Cha; A27 is Lys, hArg, Ahc, or Cha; A28 is Leu, Ahc, or Cha; A29 is Gln, Ahc, or Aib; A31 is Val, Leu, Nle, Ahc, or Cha; R1 is H; R2 is H; and R3 is NH2; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group B is where at least one of A7, A11, A15, A23, A24, A27, A28, or A31 is Cha.
Another preferred group of peptides of Group B is where at least one of A16, A17, A19, A29, or A34 is Aib.
Preferred peptides of formula (I) are [Ahc7,11]hPTH(1-34)NH2; [Ahc7,11, Nle8,18, Tyr34]hPTH(1-34)NH2; [Ahc11]hPTH(1-34)NH2; [Ahc7,11,15]hPTH(1-34)NH2; [Ahc7]hPTH(1-34)NH2; [Ahc23]hPTH(1-34)NH2; [Ahc24]hPTH(1-34)NH2; [Nle8,18, Ahc27]hPTH(1-34)NH2; [Ahc28]hPTH(1-34)NH2; [Ahc31]hPTH(1-34)NH2; [Ahc24,28,31]hPTH(1-34)NH2; [Ahc24,28,31, Lys30]hPTH(1-34)NH2; [Ahc28,31]hPTH(1-34)NH2; [Ahc15]hPTH(1-34)NH2; [Ahc24,27, Aib29, Lys30]hPTH(1-34)NH2; [Ahc24,27, Aib29, Lys30, Leu31]hPTH(1-34)NH2; [Ahc5]hPTH(1-34)NH2; [Ahc12]hPTH(1-34)NH2; [Ahc27]hPTH(1-34)NH2; [Ahc29]hPTH(1-34)NH2; [Ahc24,27]hPTH(1-34)NH2; [Ahc24,27, Aib29]hPTH(1-34)NH2; [Ahc24, Aib29]hPTH(1-34)NH2; [Ahc27, Aib29]hPTH(1-34)NH2; [Ahc18]hPTH(1-34)NH2; [Ahc8]hPTH(1-34)NH2; [Ahc18,27, Aib29]hPTH(1-34)NH2; or [Ahc18,24,27, Aib29]hPTH(1-34)NH2; [Ahc22, Leu27, Aib29]hPTH(1-34)NH2; [Ahc24, Leu27, Aib29]hPTH(1-34)NH2; [Ahc22]hPTH(1-34)NH2; and [Acc22, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
The invention also features peptides of the following formulae: [Cha22,23, Glu25, Lys26,30, Leu28, Aib29]hPTHrP(1-34)NH2; [Cha22,23, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,30,31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,30,31, Lys26]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Cha15, Glu22,25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26, Leu28,31, Aib29, Nle30]hPTHrP(1-34)NH2; [Cha22,23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26, Nle30]hPTHrP(1-34)NH2; [Cha7,11,15]hPTHrP(1-34)NH2; [Cha7,8,15]hPTHrP(1-34)NH2; [Glu22, Cha23, Aib25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Glu22, Cha23, Aib25,29, Lys26, Leu28]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Aib25,29, Lys26]hPTHrP(1-34)NH2; [Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26, Leu28,31, Aib29, Nle30]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Aib29, Leu31]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Aib29,30]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Aib26,29, Lys30)]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Leu28, Aib29]hPTHrP(1-34)NH2; or [Leu27, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
The following are examples of the peptides of the invention covered by the above formula: [Glu22,25, Leu23,28, Lys26,30, Aib29, Ahc31]hPTHrP(1-34)NH2; [Glu22,25, Ahc23, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Ahc30]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Ahc24, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25, Lys26,30, Ahc27]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Aib25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2; [Acc22, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,31, Lys26,30, Ahc28, Aib29]hPTHrP(1-34)NH2; [Cha22, Ahc23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Ahc22,24,27, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Ahc24,27, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24,27, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Ahc18,24,27, Glu22, Cha23, Lys25,26, Leu28, Aib29]hPTHrP(1-34)NH2; [Glu22, Cha23, Ahc24, Lyc25,26, Leu28, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Ahc27, Aib29, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25, Leu23,28,31, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Cha15, Glu22,25, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Cha22, Ahc23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22, Ahc23, Aib25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26,30, Ahc29]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Ahc24, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Ahc24,27, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Ahc24,27, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Ahc22,24,27, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Aib25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2; [Ahc22,27, Leu23,28,31, Aib25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24,27, Lys25,26,30, Aib29]hPTHrP 1-34)NH2; [Glu22, Leu23,28, Ahc24,27, Lys25,26,30, Aib29]hPTHrP(1-34)NH2; [Glu22, Cha23, Ahc24,27, Lys25,26,30, Leu28, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Ahc24,27, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22, Cha23, Ahc24,27, Lys25,26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24,27, Lys25,26, Aib29, ]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Ahc24,27, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Glu22, Cha23, Ahc24,26, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22, Cha23, Ahc24,27, Lys25,26, Leu28, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Lys25,26, Ahc27, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Lys25,26, Acc27, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Lys25,26,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Lys25,28,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Glu22, Cha23, Ahc24, Lys25,26, Leu28, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Aib29, Ahc30]hPTHrP(1-34)NH2; [Aib22,29, Leu23,28,31, Glu25, Lys26,30]hPTHrP(1-34)NH2; [Cha22, Ahc23, Glu25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Acc24, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2; [Cha22, Leu23,31, Glu25,29, Lys26,30, Ahc28]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26, Ahc30]hPTHrP(1-34)NH2; [Cha22, Leu23,28, Glu25,29, Lys26,30, Ahc31]hPTHrP(1-34)NH2; [Glu22,29, Ahc23, Aib25, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Ahc22, Leu23,28,31, Aib25, Lys26,30, Glu29]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Ahc24, Aib25, Lys26,30]hPTHrP(1-34)NH2; [Glu22,29, Leu23,31, Aib25, Lys26,30, Ahc28]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28, Aib25, Lys26,30, Ahc31]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25, Lys26, Ahc30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Ahc27, Aib30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Ahc24, Lys26, Aib30]hPTHrP(1-34)NH2; [Ahc22, Leu23,28,31, Glu25,29, Lys26, Aib30]hPTHrP(1-34)NH2; [Ahc22, Leu23,28, Glu25,29, Lys26,30,31]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28, Lys26,31, Ahc30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28, Lys26,30,31, Ahc27]hPTHrP(1-34)NH2; [Ahc22, Cha23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Ahc22, Cha23, Lys25,26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Ahc22, Cha23, Lys25,26, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Ahc22, Leu23,28, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Ahc22, Leu23,28, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2; [Ahc22,24, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Ahc22,24,Leu23,28,31, Lys25,26,30, Aib29]hPTHrP(1-34)NH2; [Ahc22,24, Leu23,28,31, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Ahc22,24, Leu23,28, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Ahc22,24, Leu23,28, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24, Lys25,26,30, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Ahc24, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24, Arg25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Ahc24, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, Ahc23, Aib25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Glu22, Ahc23, Aib25,29, Lys26, Leu28]hPTHrP(1-34)NH2; [Glu22, Ahc23,31, Aib25,29, Lys26, Leu28]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Aib25,29, Lys26,30, Ahc31]hPTHrP(1-34)NH2; [Glu22, Leu23,28, Aib25,29, Lys26, Ahc31]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28, Acc24,31, Lys26,30, Aib29]hPTHrP(1-34)NH2; or [Glu22, Leu23,28, Ahc24,31, Lys25,26, Aib29]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Ahc24, Aib25,29, Lys26,30]hPTHrP(1-34)NH2; or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to peptide variants of PTH(1-34) of the following generic formula: 
wherein
A1 is Ser, Ala, or Dap;
A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynaphthylalkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that (i) at least one of A5, A7, A8, A11, A15, A18, A21, A23, A24, A27, a28, and A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib; or that (ii) at least A1 is Dap, A7 is xcex2-Nal, Trp, Pal, Phe, or p-X-Phe, A15 is xcex2-Nal, Trp, Pal, Phe, or p-X-Phe, A27 is hArg, or A31 is Nle; or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to peptide variants of PTH(1-34) of the following formula (II): 
wherein
A1 is Ser, Ala, or Dap;
A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynaphthylalkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that (i) at least one of A5, A7, A8, A11, A15, A18, A21, A23, A24, A27, A28, and A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib; and the peptide is not [Aib12, Tyr34]hPTH(1-34)NH2. or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of formula (II), designated Group (i) is where at least one of A7, A11, A15, A23, A24, A27, A28, and A31 is Cha; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group (i), designated Group (ii), is where A3 is Ser; A5 is Ile; A7 is Leu or Cha; A8 is Met, Nva, Leu, Val, Ile, or Nle; A11 is Leu or Cha; A12 is Gly; A15 is Leu or Cha; A16 is Asn or Aib; A17 is Ser; A18 is Met or Nle; A21 is Val; A27 is Lys, hArg, or Cha; A32 is His; A31 is Val, Nle, or Cha; A33 is Asn; A34 is Phe, Tyr, Amp, or Aib; R1 is H; R2 is H; and R3 is NH2; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group (ii), designated Group (iii), is where at least one of A7 and A11 is Cha; or a pharmaceutically acceptable salt thereof.
Preferred peptides of Group (iii) are [Cha7,11]hPTH(1-34)NH2, [Cha7,11, Nle8,18, Tyr34]hPTH(1-34)NH2; [Cha11]hPTH(1-34)NH2; [Cha7,11,15]hPTH(1-34)NH2; and [Cha7]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
Another preferred group of peptides of Group (ii), designated Group (iv), is where at least one of A15, A23, A24, A27, A28, and A31 is Cha; or a pharmaceutically acceptable salt thereof.
Preferred peptides of Group (iv) are [Cha23]hPTH(1-34)NH2, [Cha24]hPTH(1-34)NH2, [Nle8,18, Cha27]hPTH(1-34)NH2, [Cha28]hPTH(1-34)NH2, [Cha31]hPTH(1-34)NH2, [Cha24,28,31]hPTH(1-34)NH2; [Cha24,28,31, Lys30]hPTH(1-34)NH2; [Cha28,31]hPTH(1-34)NH2; and [Cha15]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
Another preferred group of peptides of formula (II), designated Group (v), is where at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group (v), designated Group (vi), is where A3 is Ser or Aib; A5 is Ile; A7 is Leu or Cha; A8 is Met, Nva, Leu, Val, Ile, or Nle; A11 is Leu or Cha; A15 is Leu or Cha; A16 is Asn or Aib; A18 is Met, Aib, or Nle; A21 is Val; A27 is Lys, Aib, Leu, hArg, or Cha; A31 is Val, Nle, or Cha; A32 is His; A33 is Asn; A34 is Phe, Tyr, Amp, or Aib; R1 is H; R2 is H; and R3 is NH2; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group (vi), designated Group (vii), is where at least one of A3, A12, A16, A17, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
Preferred peptides of Group (vii) are [Aib16]hPTH(1-34)NH2, [Aib19]hPTH(1-34)NH2, [Aib34]hPTH(1-34)NH2; [Aib16,19]hPTH(1-34)NH2; [Aib3]hPTH(1-34)NH2; [Aib17]hPTH(1-34)NH2; and [Aib12]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
Another preferred group of peptides of formula (II), designated Group (viii), is where at least one of A7, A11, A15, A23, A24, A27, A28, and A31 is Cha and at least of A3, A12, A16, A17, A18, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group (viii), designated Group (ix), is where A3 is Ser or Aib; A5 is Ile; A7 is Leu or Cha; A8 is Met, Nva, Leu, Val, Ile, or Nle; A11 is Leu or Cha; A15 is Leu or Cha; A16 is Asn or Aib; A18 is Met, Aib, or Nle; A21 is Val; A27 is Lys, Aib, Leu, hArg, or Cha; A31 is Val, Nle, or Cha; A32 is His; A33 is Asn; A34 is Phe, Tyr, Amp, or Aib; R1 is H; R2 is H; and R3 is NH2; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group (ix), designated Group (x), is where at least one of A7 and A11 is Cha and at least one of A16, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
Preferred peptides of Group (x) are [Cha7,11, Nle8,18, Aib16,19, Tyr34]hPTH(1-34)NH2, [Cha7,11, Nle8,18,31, Aib16,19, Tyr34]hPTH(1-34)NH2; [Cha7,11, Aib19]hPTH(1-34)NH2; [Cha7,11, Aib16]hPTH(1-34)NH2; [Cha7,11, Nle8,18, Aib34]hPTH(1-34)NH2; or [Cha7,11, Aib19, Lys30]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
Another preferred group of peptides of Group (ix), designated Group (xi), is where at least one of A24, A28, and A31 is Cha and at least one of A16 and A17 is Aib; or a pharmaceutically acceptable salt thereof.
Preferred peptides of Group (xi) are [Cha28, Nle8,18, Aib16,19, Tyr34]hPTH(1-34)NH2, and [Cha28, Aib16,19]PTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention is directed to a peptide of the formula (III): 
wherein
A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Ile, Nle, Cha, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is H, OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynaphthylalkyl;
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that at least A1 is Dap, A7 is xcex2-Nal, Trp, Pal, Phe, or p-X-Phe; A15 is xcex2-Nal, Trp, Pal, Phe, or p-X-Phe, A27 is hArg, or A31 is Nle; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of formula (III) is where A1 is Ser, Gly, or Dap; A3 is Ser or Aib; A8 is Met, Nva, Leu, Val, Ile, or Nle; A16 is Asn or Aib; A18 is Met, Aib, or Nle; A21 is Val; A27 is Lys, Aib, Leu, hArg, or Cha; A31 is Val, Nle, or Cha; A32 is His; A33 is Asn; A34 is Phe, Tyr, Amp, or Aib; R1 is H; R2 is H; and R3 is NH2; or a pharmaceutically acceptable salt thereof.
Preferred peptides of the immediately foregoing peptides are [Nle31]hPTH(1-34)NH2, [hArg27]hPTH(1-34)NH2, and [Dap1, Nle8,18, Tyr34]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention is directed to a peptide of the formula (IV): 
wherein
A1 is Ala, Ser, or Dap;
A3 is Ser or Aib;
A5 is His, Ile, or Cha;
A7 is Leu, Cha, Nle, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Leu, Met, or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Phe, or xcex2-Nal;
A12 is Gly or Aib;
A14 is Ser or His;
A15 is Ile, or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib, or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, or Cha;
A23 is Phe, Leu, Lys, or Cha;
A24 is Leu, Lys, or Cha;
A25 is His, Aib, or Glu;
A26 is His, Aib, or Lys;
A27 is Leu, Lys, or Cha;
A28 is Ile, Leu, Lys, or Cha;
A29 is Ala, Glu, or Aib;
A30 is Glu, Cha, Aib, or Lys;
A31 is Ile, Leu, Cha, Lys, or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12, hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A5, A7, A8, A11, A15, A,18, A22, A23, A24, A27, A28, A30, or A31 is Cha, or at least one of A3, A12, A,16, A17, A18, A19, A22, A25, A26, A29, A30, or A34 is Aib; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of formula (IV) is where A22 is Phe or Cha; A23 is Phe or Cha; A25 is His; A26 is His; A27 is Leu or Cha; A28 is Ile or Cha; A29 is Ala; A30 is Glu or Lys; A31 is Ile or Cha; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof. Two preferred groups of peptides of the immediately foregoing group of peptides is where at least one of A7 and A11 is Cha; or where at least one of A16 or A19 is Aib; or a pharmaceutically acceptable salt thereof.
Another preferred group of peptides of formula (IV), is where A22 is Glu, Aib, or Cha; A23 is Leu, Lys, or Cha; A25 is Aib or Glu; A26 is Aib or Lys; A28 is Leu, Lys, or Cha; A29 is Glu or Aib; A30 is Cha, Aib, or Lys; A31 is Leu, Cha, or Lys; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof. Two preferred groups of peptides of the immediately foregoing group of peptides is where at least one of A7 and A11 is Cha; or where at least one of A16 or A19 is Aib; or a pharmaceutically acceptable salt thereof.
In another aspect, this invention is directed to a peptide of the formula (V): 
wherein
A1 is Ala, Ser or Dap;
A3 is Ser or Aib;
A5 is His, Ile or Cha;
A7 is Leu, Cha, Nle, xcex2-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen or CH3;
A8 is Leu, Met or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Phe or xcex2-Nal;
A12 is Gly or Aib;
A14 is Ser or His;
A15 is Ile or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, Acc or Cha;
A23 is Phe, Leu, Lys, Acc or Cha;
A24 is Leu, Lys, Acc or Cha;
A25 is His, Aib or Glu;
A26 is His, Aib or Lys;
A27 is Leu, Lys, Acc or Cha;
A28 is Ile, Leu, Lys, Acc or Cha;
A29 is Ala, Glu or Aib;
A30 is Glu, Cha, Aib, Acc or Lys;
A31 is Ile, Leu, Cha, Lys, Acc or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12, hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A23, A24, A27, A28, or A31 is Lys; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of formula (V) is where A22 is Glu, Aib, Acc, or Cha; A23 is Leu, Lys, Acc, or Cha; A25 is Aib or Glu; A26 is Aib or Lys; A28 is Leu, Lys, Acc, or Cha; A29 is Glu or Aib; A30 is Cha, Aib, Acc, or Lys; A31 is Leu, Cha, Acc, or Lys; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof. Two preferred groups of peptides of the immediately foregoing group of peptides is where at least one of A7 and A11 is Cha; or where at least one of A16 or A19 is Aib; or a pharmaceutically acceptable salt thereof.
The following are examples of peptides of this invention as encompassed by formula (II): [Cha7]hPTH(1-34)NH2; [Cha11]hPTH(1-34)NH2; [Cha15]hPTH(1-34)NH2; [Cha7,11]hPTH(1-34)NH2; [Cha7,11Nle8,18, Tyr34]hPTH(1-34)NH2; [Cha23]hPTH(1-34)NH2; [Cha24]hPTH(1-34)NH2; [Nle8,18, Cha27]hPTH(1-34)NH2; [Cha28]hPTH(1-34)NH2; [Cha31]hPTH(1-34)NH2; [Cha27]hPTH(1-34)NH2; [Cha27,29]hPTH(1-34)NH2; [Cha28]bPTH(1-34)NH2; [Cha28]rPTH(1-34)NH2; [Cha24,28,31]hPTH(1-34)NH2; [Aib16]hPTH(1-34)NH2; [Aib19]hPTH(1-34)NH2; [Aib34]hPTH(1-34)NH2; [Aib16,19]hPTH(1-34)NH2; [Aib16,19,34]bPTH(1-34)NH2; [Aib16,34]hPTH(1-34)NH2; [Aib19,34]hPTH(1-34)NH2; [Cha7,11Nle8,18, Aib16,19, Tyr34]hPTH(1-34)NH2; [Cha7,11, Nle8,18,31, Aib16,19, Tyr34]hPTH(1-34)NH2; [Cha7, Aib16]hPTH(1-34)NH2; [Cha11, Aib16]hPTH(1-34)NH2; [Cha7, Aib34]hPTH(1-34)NH2; [Cha11, Aib34]hPTH(1-34)NH2; [Cha27, Aib16]hPTH(1-34)NH2; [Cha27, Aib34]hPTH(1-34)NH2; [Cha28, Aib16]hPTH(1-34)NH2; [Cha28, Aib34]hPTH(1-34)NH2; [Nle31]hPTH(1-34)NH2; [hArg27]hPTH(1-34)NH2; [Dap1, Nle8,18, Tyr34]hPTH(1-34)NH2; [Nle31]bPTH(1-34)NH2; [Nle31]rPTH(1-34)NH2; [hArg27]bPTH(1-34)NH2; [hArg27]rPTH(1-34)NH2; [Cha7,11, Aib19, Lys30]hPTH(1-34)NH2; [Aib12]hPTH(1-34)NH2; [Cha24,28,31, Lys30]hPTH(1-34)NH2; [Cha28,31]hPTH(1-34)NH2; [Cha7,11, Nle8,18, Aib34]hPTH(1-34)NH2; [Aib3]hPTH(1-34)NH2; [Cha8]hPTH(1-34)NH2; [Cha15]hPTH(1-34)NH2; [Cha7,11, Aib19]hPTH(1-34)NH2; [Cha7,11, Aib16]hPTH(1-34)NH2; [Aib17]hPTH(1-34)NH2; [Cha5]hPTH(1-34)NH2; [Cha7,11,15]hPTH(1-34)NH2; [Cha7,11, Nle8,18, Aib19, Tyr34]hPTH(1-34)NH2; [Cha7,11, Nle8,18, Aib19, Lys30, Tyr34]hPTH(1-34)NH2; [Cha7,11,15]hPTH(1-34)NH2; [Aib17]hPTH(1-34)NH2; [Cha7,11, Leu27]hPTH(1-34)NH2; [Cha7,11,15, Leu27]hPTH(1-34)NH2; [Cha7,11,27]hPTH(1-34)NH2; [Cha7,11,15,27]hPTH(1-34)NH2; [Trp15]hPTH(1-34)NH2; [Nal15]hPTH(1-34)NH2; [Trp15, Cha23]hPTH(1-34)NH2; [Cha15,23]hPTH(1-34)NH2; [Phe7,11]hPTH(1-34)NH2; [Nal7,11]hPTH(1-34)NH2; [Trp7,11]hPTH(1-34)NH2; [Phe7,11,15]hPTH(1-34)NH2; [Nal7,11,15]hPTH(1-34)NH2; [Trp7,11,15]hPTH(1-34)NH2; and [Tyr7,11,15]hPTH(1-34)NH2.
The following are specific examples of peptides encompassed by one or more of formulas (III) to (V), hereinabove: [Cha7]hPTHrP(1-34)NH2; [Cha11]hPTHrP(1-34)NH2; [Cha7,11]hPTHrP(1-34)NH2; [Aib16, Tyr34hPTHrP(1-34)NH2; [Aib19]hPTHrP(1-34)NH2; [Aib16,19]hPTHrP(1-34)NH2; [Cha7,11, Aib16hPTHrP(1-34)NH2; [Cha7,11, Aib19]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26,27,30]hPTHrP(1-34)NH2; [Cha22,23, Glu25,29, Leu28,31, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25,29, Lys23,26,30, Leu28,31]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Cha30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Aib30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,31, Lys26,28,30]hPTHrP(1-34) NH2; [Cha22,23,24,27,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25,29, Cha23,24,28,31, Lys26,27,30]hPTHrP(1-34)NH2; [Glu22,25,29, Cha23,24,27,31, Lys26,28,30]hPTHrP(1-34)NH2; [Glu22,25,29, Lys23,26,30, Cha24,27,28,31]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26,27,30]hPTHrP(1-34)NH2; [Cha22, Leu23,31, Glu25,29, Lys26,28,30]hPTHrP(1-34)NH2; [Cha22, Lys23,26,30, Glu25,29, Leu28,31]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26, Aib30]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26,27,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Lys23,26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,31, Lys26,28,30, Aib29]hPTHrP(1-34)NH2; [Cha7,11, Glu22,25,29, Leu23,28,31, Lys26,30]hPTHrP(1-34)NH2; [Cha7,11,22, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Cha7,11, Glu22,25,29, Leu23,28,31, Lys26,27,30]hPTHrP(1-34)NH2; [Cha7,11,22,23, Glu25,29, Leu28,31, Lys26,30]hPTHrP(1-34)NH2; [Cha7,11, Glu22,25,29, Lys23,26,30, Leu28,31]hPTHrP(1-34)NH2; [Cha7,11, Glu22,25,29, Leu23,31, Lys26,28,30]hPTHrP(1-34)NH2; [Cha7,11, Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2; [Cha7,11, Glu22,25,29, Leu23,28,31, Lys26, Aib30]hPTHrP(1-34)NH2; [Cha15, Glu22,25,29, Leu23,28,31, Lys26,30]hPTHrP(1-34)NH2; [Cha15,22, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Cha15, Glu22,25,29, Leu23,28,31, Lys26,27,30]hPTHrP(1-34)NH2; [Cha15,22,23, Glu25,29, Leu28,31, Lys26,30]hPTHrP(1-34)NH2; [Cha15, Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2; [Cha15, Glu22,25,29, Lys23,26,30, Leu28,31]hPTHrP(1-34)NH2; [Cha15, Glu22,25,29, Leu23,28,31, Lys26, Aib30]hPTHrP(1-34)NH2; [Cha15, Glu22,28,29, Leu23,31, Lys26,28,30]hPTHrP(1-34)NH2; [Cha15,30, Glu22,25,29, Leu23,28,31, Lys26]hPTHrP(1-34)NH2; [Cha7,8,22, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Cha7,8, Glu22,25,29, Leu23,28,31, Lys26,27,30]hPTHrP(1-34)NH2; [Cha7,8,22,23, Glu25,29, Leu28,31, Lys26,30]hPTHrP(1-34)NH2; [Cha7,8, Glu22,25,29, Leu23,28,31, Lys26,30]hPTHrP(1-34)NH2; [Cha7,8, Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2; [Cha7,8, Glu22,25,29, Lys23,26,30, Leu28,31]hPTHrP(1-34)NH2; [Cha7,8, Glu22,25,29, Leu23,28,31, Lys26, Aib30]hPTHrP(1-34)NH2; [Cha7,8, Glu22,25,29, Leu23,31, Lys26,28,30]hPTHrP(1-34)NH2; [Cha7,8,30, Glu22,25,29, Leu23,28,31, Lys26]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11,22, Met8, Asn10, His14, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25,29, Leu23,28,31, Lys26,27,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25,29, Leu23,31, Lys26,28,30]hPTHrP(1-34)NH2; Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,2,29, Lys23,26,30, Leu28,31]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25,29, Leu23,28,31, Lys26, Aib30]PTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11,22,23, Met8, Asn10, His14, Glu25,29, Leu28,31, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11,15, Met8, Asn10, His14]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11, His14, Aib16]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,28,31, His14, Cha22,23, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25,29, Leu23,28,31, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, His14, Cha15, Glu22,25,29, Leu23,28,31, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Cha7,8, Asn10, His14, Glu22,25,29, Leu23,28,31, Lys26,30]hPTHrP(1-34)NH2; (1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys24,26,30]hPTHrP(1-34)NH2; [Aib22, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Aib26, Lys30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,Lys26,30,31]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Cha22, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,28,31, His14, Glu22,25,29, Lys23,26,30]PTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Glu22,25,29, Lys26,27,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,31, His14, Glu22,25,29, Lys26,28,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Glu22,25, Aib29, Lys26,30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Glu22,25,29, Lys26, Aib30]hPTHrP(1-34)NH2; or [Ser1, Ile5, Met8]hPTHrP(1-34)NH2. [Glu22,25, Ahc23, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28, Aib29, Ahc31]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Leu28, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Ahc22, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Aib29, Ahc30]hPTHrP(1-34)NH2; [Glu22,25, Cha23, Lys26,30, Aib29, Leu31]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Ahc24, Lys26,30, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,31, Lys26,30, Ahc28, Aib29]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Lys26, Aib29,30]hPTHrP(1-34)NH2; [Aib22,29, Leu23,28,31, Glu25, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28,31, Aib26,29, Lys30]hPTHrP(1-34)NH2; [Cha22, Ahc23, Glu25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Ahc24, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2; (Cha22, Leu23,31, Glu25,29, Lys26,30, Ahc28]hPTHrP(1-34)NH2; [Cha22, Leu23,28,31, Glu25,29, Lys26, Leu28, Ahc30]hPTHrP(1-34)NH2; [Cha22,23, Glu25,29, Lys26,30, Leu31]hPTHrP(1-34)NH2; [Cha22, Leu23,28, Glu25,29, Lys26,30, Ahc31]hPTHrP(114 34)NH2; [Cha22,23, Glu25,29, Lys26,30, Leu31]hPTHrP(1-34)NH2; [Cha22,23, Glu25,29, Lys26,30, Leu28]hPTHrP(1-34)NH2; [Cha22,23, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22, Leu23,28,31, Aib25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22,29, Ahc23, Aib25, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Ahc22, Leu23,28,31, Aib25, Lys26,30, Glu29]hPTHrP(1-34)NH2; [Aib22,25, Leu23,28,31, Lys26,30, Glu29]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Ahc24, Aib25, Lys26,30]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25,26, Lys30]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25, Lys26,30, Ahc27]hPTHrP(1-34)NH2; [Glu22,29, Leu23,31, Aib25, Lys26,30, Ahc28]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28, Aib25, Lys26,30, Ahc31]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25,30, Lys26]hPTHrP(1-34)NH2; [Glu22,29, Leu23,28,31, Aib25, Lys26, Ahc30]hPTHrP(1-34)NH2; [Glu22,29, Cha23, Aib25, Lys26,30, Leu28,31]hPTHrP(1-34)NH2; [Glu22,29, Cha23, Aib25, Lys26,30, Leu31]hPTHrP(1-34)NH2; [Glu22,29, Cha23, Aib25, Lys26,30]hPTHrP(1-34)NH2; [Glu22,29, Cha23, Aib25, Lys26,30, Leu28]hPTHrP(1-34)NH2; [Glu22,25,29, Cha23, Lys26, Leu28,31, Aib30]hPTHrP(1-34)NH2; [Glu22,25,29, Cha23, Lys26, Aib30, Leu31]hPTHrP(1-34)NH2; [Glu22,25,29, Cha23, Lys26, Aib30]hPTHrP(1-34)NH2; [Glu22,25,29, Cha23, Lys26, Leu28, Aib30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Ahc27, Aib30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Ahc24, Lys26, Aib30]hPTHrP(1-34)NH2; [Ahc22, Leu23,28,31, Glu25,29, Lys26, Aib30]hPTHrP(1-34)NH2; [Aib22,30, Leu23,28,31, Glu25,29, Lys26]hPTHrP(1-34)NH2; [Glu22,25, Leu23,28, Lys26,30,31, Aib29]hPTHrP(1-34)NH2; [Cha22, Leu23,28, Glu25,29, Lys26,30,31]hPTHrP(1-34)NH2; [Ahc22, Leu23,28, Glu25,29, Lys26,30,31]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28, Lys26,30,31, Ahc30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28,31, Lys26, Ahc30]hPTHrP(1-34)NH2; [Ahc22, Leu23,28,31, Glu25,29, Lys26,30]hPTHrP(1-34)NH2; [Glu22,25,29, Leu23,28, Lys26,30,31, Ahc27]hPTHrP(1-34)NH2.
In another aspect, the present invention is directed to a method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, as defined hereinabove.
In another aspect, the present invention is directed to a method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, as defined hereinabove.
In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound of formula (I), (II), (Ill), (IV) or (V) or a pharmaceutically acceptable salt thereof as defined hereinabove, a bisphosphonate or calcitonin and a pharmaceutically acceptable carrier or diluent.
In another aspect, the present invention is directed to a method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention is directed to a method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of the formula [Glu22,25, Leu2328,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt there
In another aspect, the present invention is directed to a pharmaceutical composition comprising a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
In another aspect, the present invention is directed to a pharmaceutical composition comprising a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.
In another aspect, the present invention is directed to a method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula (VI): 
wherein
A1 is Ala, Ser, or Dap;
A3 is Ser or Aib;
A5 is His, Ile, Acc, or Cha;
A7 is Leu, Cha, Nle, xcex2-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Leu, Met, Acc, or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Acc, Phe, or xcex2-Nal;
A12 is Gly, Acc, or Aib;
A14 is Ser or His;
A15 is Ile, Acc, or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib, Acc, or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, Acc, or Cha;
A23 is Phe, Leu, Lys, Acc, or Cha;
A24 is Leu, Lys, Acc, or Cha;
A25 is His, Lys, Aib, Acc, or Glu;
A26 is His, Aib, Acc, or Lys;
A27 is Leu, Lys, Acc, or Cha;
A28 is Ile, Leu, Lys, Acc, or Cha;
A29 is Ala, Glu, Acc, or Aib;
A30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
A31 is Ile, Leu, Cha, Lys, Acc, or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12, hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 naphthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynaphthylalkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A5, A7, A8, A11, A12, A15, A18, A22, A23, A24, A25, A26, A27, A28, A29, A30, or A31 is Acc; or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention is directed to a method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of formula (VI), as defined hereinabove.
In another aspect, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a peptide of formula (VI), as defined hereinabove.
In another aspect, the present invention is directed to a pharmaceutical composition comprising a bisphosphonate or calcitonin, a pharmaceutically acceptable carrier or diluent, and a peptide of formula (VI), as defined hereinabove.
With the exception of the N-terminal amino acid, all abbreviations (e.g. Ala or A1) of amino acids in this disclosure stand for the structure of xe2x80x94NHxe2x80x94CH(R)xe2x80x94COxe2x80x94, wherein R is a side chain of an amino acid (e.g., CH3 for Ala). For the N-terminal amino acid, the abbreviation stands for the structure of xe2x95x90Nxe2x80x94CH(R)xe2x80x94COxe2x80x94, wherein R is a side chain of an amino acid. xcex2-Nal, Nle, Dap, Cha, Nva, Amp, Pal, Ahc, and Aib are the abbreviations of the following xcex1-amino acids: xcex2-(2-naphthyl)alanine, norleucine, xcex1,xcex2-diaminopropionic acid, cyclohexylalanine, norvaline, 4-amino-phenylalanine, xcex2-(3-pyridinyl)alanine, 1-amino-1-cyclo-hexanecarboxylic acid, and xcex1-aminoisobutyric acid, respectively. What is meant by Acc is an amino acid selected from the group of 1-amino-1-cyclopropanecarboxylic acid; 1-amino-1-cyclobutanecarboxylic acid 1-amino-1-cyclopentanecarboxylic acid; 1-amino-1-cyclohexanecarboxylic acid; 1-amino-1-cycloheptanecarboxylic acid; 1-amino-1-cyclooctanecarboxylic acid; and 1-amino-1-cyclononanecarboxylic acid. In the above formula, hydroxyalkyl, hydroxyphenyl-alkyl, and hydroxynaphthylalkyl may contain 1-4 hydroxy substituents. Also, COE1 stands for xe2x80x94Cxe2x95x90O.E1. Examples of xe2x80x94Cxe2x95x90O.E1 include, but are not limited to, acetyl and phenylpropionyl.
A peptide of this invention is also denoted herein by another format, e.g., [Acc7,11]hPTH(1-34)NH2, with the substituted amino acids from the natural sequence placed between the second set of brackets (e.g., Ahc7 for Leu7, and Ahc11 for Leu11 in hPTH). The abbreviation hPTH stands for human PTH, hPTHrP for human PTHrP, rPTH for rat PTH, and bPTH for bovine PTH. The numbers between the parentheses refer to the number of amino acids present in the peptide (e.g., hPTH(1-34) is amino acids 1 through 34 of the peptide sequence for human PTH). The sequences for hPTH(1-34), hPTHrP(1-34), bPTH(1-34), and rPTH(1-34) are listed in Nissenson, et al., Receptor, 3:193 (1993). The designation xe2x80x9cNH2xe2x80x9d in PTH(1-34)NH2 indicates that the C-terminus of the peptide is amidated. PTH(1-34), on the other hand, has a free acid C-terminus.
Each of the peptides of the invention is capable of stimulating the growth of bone in a subject (i.e., a mammal such as a human patient). Thus, it is useful in the treatment of osteoporosis and bone fractures when administered alone or concurrently with antiresorptive therapy, e.g., bisphosphonates and calcitonin.
The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids).
A therapeutically effective amount of a peptide of this invention and a pharmaceutically acceptable carrier substance (e.g., magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a Michelle) together form a therapeutic composition (e.g., a pill, tablet, capsule, or liquid) for administration (e.g., orally, intravenously, transdermally, pulmonarily, vaginally, subcutaneously, nasally, iontophoretically, or by intratracheally) to a subject. The pill, tablet, or capsule that is to be administered orally can be coated with a substance for protecting the active composition from the gastric acid or intestinal enzymes in the stomach for a period of time sufficient to allow it to pass undigested into the small intestine. The therapeutic composition can also be in the form of a biodegradable or nonbiodegradable sustained release formulation for subcutaneous or intramuscular administration. See, e.g., U.S. Pat. Nos. 3,773,919 and 4,767,628 and PCT Application No. WO 94/15587. Continuous administration can also be achieved using an implantable or external pump (e.g., INFUSAID(trademark) pump). The administration can also be conducted intermittently, e.g., single daily injection, or continuously at a low dose, e.g., sustained release formulation.
The dose of a peptide of the present invention for treating the above-mentioned diseases or disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian.
Also contemplated within the scope of this invention is a peptide covered by the above generic formula for use in treating diseases or disorders associated with deficiency in bone growth or the like, e.g., osteoporosis or fractures.